Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue, typically as the result of inflammation or damage. Fibrosis encompasses the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. Fibrosis is similar to the process of scarring, in that both involve stimulated cells (e.g., fibroblasts) laying down connective tissue, including collagen and glycosaminoglycans.
Fibrosis can be considered as a scarring process in response to chronic diseases where excessive extracellular matrix (ECM) deposition leads to irreversible tissue damage and failure or disturbance of proper organ function. The pathophysiology of fibrosis has generally been studied in the context of the particular organ or tissue affected, including lung, kidney, liver, heart and skin. Loss of metabolic homeostasis and chronic low-grade inflammation may play a role in the pathogenesis of fibrosis. Fibrogenesis is a dynamic process and occurs in four phases: i) initiation, due to injury of the organ/tissue; ii) inflammation and activation of effector cells; iii) enhanced synthesis of ECM; and iv) deposition of ECM with progression to end-organ failure.
Fibrosis can occur in many tissues within the body. Examples include pulmonary fibrosis (lungs), idiopathic pulmonary fibrosis (lungs), cystic fibrosis (lungs), progressive massive fibrosis (lungs), liver fibrosis, cirrhosis (liver), steatohepatitis (fatty liver disease), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), endomyocardial fibrosis (heart), myocardial infarction (heart), atrial fibrosis (heart), medastinal fibrosis (soft tissue of mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis (soft tissue of the retroperitoneum), nephrogenic systemic fibrosis (skin), keloid (skin), Crohn's disease (intestine), scleroderma/systemic sclerosis (skin, lungs), arthrofibrosis (knee, shoulder, other joints), Peyronie's disease (penis), Dupuytren's contracture (hands, fingers), adhesive capsulitis (shoulder), kidney fibrosis, and focal and segmental glomerulosclerosis (kidney).
One of the major complications of insulin resistance and metabolic syndrome is nonalcoholic fatty liver disease (NAFLD), which can progress from fatty liver to liver inflammation (NASH) and liver fibrosis. It is believed that due to intestinal barrier leakage, accompanied by overgrowth and changes in the composition of gut flora, bacterial components travel through the portal vein into the liver, where they encounter toll like receptors (TLRs).
TLRs are a family of receptors imperative for the innate immune response against microbial invasion. TLRs can be divided into two major subgroups based on their cellular localization. Plasma membrane expressed TLRs include TLR1, TLR2, TLR4, TLR5, and TLR6, whereas the intracellular TLRs include TLR3, TLR7, TLR8, and TLR9. The interaction between TLRs with their cognate agonists instigates a cascade of cues which include recruitment of the adaptor molecules MyD88/TRIF and downstream phosphorylation of MAPK kinases and NF-κB. These events culminate in the secretion of proinflammatory cytokines, including IL-12/23, IL-6 and TNF-α. TLR2 forms a heterodimer with TLR1 which recognizes bacterial triacylated lipopeptides, and a heterodimer with TLR6 which recognizes bacterial diacylated lipopeptides. TLR4 coupled to MD2 in complex with lipopolysaccharide-binding protein (LBP) and the co-receptor CD14 bind lipopolysaccharide (LPS) from gram negative bacteria.
Liver resident kupffer and hepatic stellate cells (HSC) express TLR2 which recognize triacylated lipopeptides from Gram-negative bacteria and mycoplasma and diacylated lipopeptides from Gram-negative bacteria and mycoplasma and TLR4 and its co-receptor CD14 which recognize lipopolysaccharide (LPS) from gram-negative bacteria. Both TLR2 and TLR4 can also bind to danger associated molecular patterns released from injured tissues. These TLR2 and TLR4 complexes mediate the production of pro-inflammatory cytokines and fibrogenic response by kupffer and stellate cells. Pre-clinical studies showed that nonalcoholic steatohepatitis and liver fibrosis are inhibited in TLR2 and TLR4 deficient mice, indicating its role in disease pathogenesis. In humans, LPS plasma levels are elevated in NAFLD patients and alterations in TLR4 and CD14 genes are associated with risks of developing nonalcoholic steatohepatitis and fibrogenesis.
Monocytes are key players in the immune system, with critical roles in innate and adaptive immunity, immune surveillance and particle scavenging. Whereas a subset of monocytes is “resident” and recruited to tissues independently of inflammatory stimuli to assist in steady-state surveillance, wound-healing and resolution of inflammation, the absolute majority (80-90%) of human circulating monocytes is classified as “inflammatory”. These monocytes can sense inflammatory stimuli and quickly migrate through the vascular or lymphatic endothelium to the periphery, where they can differentiate into macrophages and dendritic cells (DCs) which cooperate with additional cell subsets (such as Th1-cells) to promote inflammation. While playing a necessary role in host defense, monocytes were nonetheless identified as critical mediators of several inflammatory diseases, including atherosclerosis, rheumatoid arthritis (RA) and multiple sclerosis (MS). Suppressing the accumulation of unwanted monocytes/macrophages in a chronically inflamed tissue has therapeutic potential, and migration inhibitors have accordingly demonstrated promising anti-inflammatory results in animal models and clinical trials.
Renal fibrosis (kidney fibrosis) is a wound healing/scarring response following kidney injury that occurs in many forms of chronic kidney disease (CKD). Following kidney injury, resident fibroblasts are activated by various pro-inflammatory and pro-fibrotic stimuli. Activated fibroblasts, also called myofibroblasts, produce excessive ECM proteins that accumulate in the interstitium, and therefore are considered a mediator of renal fibrosis. Regardless of the primary insult leading to renal fibrosis, chronic inflammation appears to be a process heralding renal fibrogenesis. Elevated levels of inflammatory markers were associated with an increased risk of developing CKD. Induction of various pro-inflammatory cytokines interleukin (IL)-6, IL-8, IL-10, chemokine (C—C motif) ligand 2 (CCL2), tumor necrosis factor-α (TNF-α) and adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) attracted the transmigration of macrophages and T cells from the circulation to the interstitium, thereby further enhancing the inflammatory state. Evidence suggests that TLRs and macrophages are associated with the pathogenesis of renal fibrosis.
Fibrosis or inflammatory diseases or disorders can cause severe morbidity and deleterious effects on patients' daily function, activity of daily living (ADL) and quality of life, and can lead to a poor prognosis. For example, idiopathic pulmonary fibrosis (IPF) is a chronic intractable disease associated with worsening and debilitating shortness of breath. IPF patients become oxygen dependent, and have an average median survival time of three years and a five year survival rate of 20% to 40% after diagnosis. Therefore, the development of new therapies for fibrosis and inflammatory diseases or disorders is needed.